Morphea, Eosinophilic Fasciitis and Cancer: A Scoping Review

Simple Summary Morphea and eosinophilic fasciitis (EF) are cutaneous autoimmune fibrosing diseases. We conducted a scoping review following PRISMA-ScR guidelines to ascertain the association between cancer and morphea/EF, focusing specifically on the paraneoplastic phenomenon, risk of subsequent cancer and development of morphea/EF as a consequence of cancer treatment. We identified that morphea patients, particularly those with generalized disease, might be at an increased risk of secondary malignancy, notably skin and pancreatic cancer. EF, on the other hand, occurred as a paraneoplastic disease in 10% of patients, primarily associated with hematologic malignancies. While reports of radiotherapy and chemotherapy-induced morphea are numerous, immunotherapy-induced morphea/EF cases are emerging. Interestingly, all immunotherapy-induced cases occurred with PD-1 inhibitors. Abstract Morphea is an autoimmune fibrotic skin disease. Eosinophilic fasciitis (EF) is considered to belong to the severe spectrum of morphea. We conducted a scoping review assessing the risk of secondary cancer among morphea/EF patients, paraneoplastic morphea/EF and morphea/EF developing secondary to cancer therapy. The search was conducted using MEDLINE, Embase, Cochrane databases for articles published from inception to September 2022 following the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR) guidelines with no language or date restrictions. Two hundred and one studies were included. Of these, 32 studies reported on secondary cancer in morphea/EF patients, 45 on paraneoplastic morphea/EF and 125 on cancer-treatment-induced morphea/EF. While the current evidence remains limited, data suggest an increased risk of secondary cutaneous and possibly pancreatic malignancy in morphea patients, particularly the generalized subtype. There were insufficient data for EF. On the other hand, paraneoplastic morphea was anecdotal, whereas several observational studies suggested that ~10% of EF cases may be paraneoplastic, primarily in the context of hematologic malignancies. Radiotherapy-induced morphea is rare, seen in ~0.2% of treated patients and is usually localized to the treatment site, except in patients with pre-existing autoimmunity. While chemotherapy-induced cases are reported, immunotherapy morphea/EF cases are emerging and are preferentially seen with PD-1 and not CTLA-4 inhibitors. This study is limited by the type of articles included (case reports, case series and observational studies), and hence, additional research on this important topic is needed.

The increased risk of malignancy in patients with systemic fibrosing chronic autoimmune diseases (e.g., SSc) has been previously described [9,10].While the underlying mechanism behind cancer predisposition in autoimmunity is unclear, multiple factors are likely to contribute, including shared risk factors, chronic inflammation, premature immunosenescence and/or impaired DNA repair/genomic mutations and therapy-related immunosuppression [11][12][13].Recently, a higher risk of cancer in patients with morphea was suggested [14].
On the other hand, immune dysregulation may also present as a paraneoplastic phenomenon, such as that seen in dermatomyositis or paraneoplastic pemphigus [15][16][17].Cancer neoantigens may drive these inflammatory signals [18].Previous studies suggested that underlying cancer may be identified in up to 10% of EF patients, and case reports of paraneoplastic morphea were also published [19].
Due to limited data, there are currently no recommendations regarding baseline or long-term screening for malignancy in morphea or EF patients.Hence, we sought to conduct a scoping review to explore the evidence to date regarding the risk of (1) secondary malignancy in morphea/EF patients, (2) paraneoplastic morphea/EF, and (3) morphea/EF arising due to cancer therapy.

Materials and Methods
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines were followed.MEDLINE, Embase and Cochrane databases were searched independently by 2 authors (MJC, AG) for original manuscripts published from inception to September 2022.The following keywords and meSH terms were searched: (localized scleroderma OR morphea or eosinophilic fasciitis) AND (carcinom* OR neoplas* OR adenocarcinom* OR cancer* OR tumor* OR tumour* OR sarcom* OR adenom* OR lymphom* OR myeloproliferative or myeloma OR immunotherapy OR immune checkpoint inhibitor OR pembrolizumab OR nivolumab OR ipilimumab OR atezolizumab OR durvalumab OR cemiplimab OR avelumab OR radiotherapy OR radiation therapy OR radiation treatment OR chemotherapy OR chemotherapeutic agent OR antineoplastic agents OR cancer treatment OR cancer therapy).The full search strategy is provided in Supplementary Materials.Inclusion criteria were articles on morphea/EF human patients who were diagnosed with cancer and/or received cancer treatment without restriction to language, study design, sample size or year of publication.Publications reporting on SSc, other conditions (e.g., graft versus host disease) and benign neoplasms were excluded.All types of articles were included except for review articles and conference abstracts.Abstracts and full texts were screened for eligibility by MJC and AG, and in case of disagreement, EN was consulted.Manual searches of references of included manuscripts were performed to reveal additional articles.The articles that were not obtained despite 2 attempts to contact authors and through inter-library loan agreement were excluded.For included articles, the following data were extracted from each study by two independent reviewers (MJC and AG): patient demographics (number of patients, age, sex, race), characteristics of morphea/EF (morphea subtype, time to disease onset), cancer treatment (type of Cancers 2023, 15, 4450 3 of 11 therapy, time to disease onset after cancer therapy initiation) and/or cancer characteristics (cancer type, time to cancer onset).The type of morphea was determined according to the Padua classification [20,21].Among morphea/EF patients who developed cancer following their diagnosis, a paraneoplastic case was determined if the authors concluded it was a paraneoplastic case and/or when the cancer occurred within 3 years of morphea/EF onset as previously defined [22].Whereas the occurrence of cancer more than 3 years after morphea/EF diagnosis was included in the risk of cancer in morphea/EF patients' section.
MJC and AG, and in case of disagreement, EN was consulted.Manual searches of references of included manuscripts were performed to reveal additional articles.The articles that were not obtained despite 2 attempts to contact authors and through inter-library loan agreement were excluded.For included articles, the following data were extracted from each study by two independent reviewers (MJC and AG): patient demographics (number of patients, age, sex, race), characteristics of morphea/EF (morphea subtype, time to disease onset), cancer treatment (type of therapy, time to disease onset after cancer therapy initiation) and/or cancer characteristics (cancer type, time to cancer onset).The type of morphea was determined according to the Padua classification [20,21].Among morphea/EF patients who developed cancer following their diagnosis, a paraneoplastic case was determined if the authors concluded it was a paraneoplastic case and/or when the cancer occurred within 3 years of morphea/EF onset as previously defined [22].Whereas the occurrence of cancer more than 3 years after morphea/EF diagnosis was included in the risk of cancer in morphea/EF patients' section.
A US population-based retrospective case-control study used insurance databases and physician billing claims (International Classification of Diseases 9th edition (ICD-9)) to investigate the risk of pancreatic cancer in patients with autoimmune diseases, including morphea.The control group was randomly selected in a ratio of 4:1 from a representative sample of Medicare-enrolled beneficiaries without cancer or from the Surveillance Epidemiology and End Results Program (SEER)-Medicare Patient Entitlement Diagnosis Summary File (PEDSF).In total, 166 morphea patients were diagnosed with pancreatic cancer (155 with pancreatic ductal adenocarcinoma).An increased risk of pancreatic cancer with an odds ratio (OR) of 1.27 (95% confidence interval (CI), 1.06-1.52)was seen, particularly for pancreatic ductal adenocarcinoma (OR 1.24; 95% CI, 1.03-1.48)when compared to the control group even after adjusting for multiple confounders (e.g., demographics, life habits and relevant chronic illnesses) [23].
A Swedish study similarly searched for incident cases of breast and gynecologic malignancies in a national population-based database among patients diagnosed with 33 autoimmune diseases, including 708 patients diagnosed with morphea based on ICD 7 to 10 codes.No increased risk of breast cancer was seen, whereas a higher-than-expected incidence of other female genital cancers (standardized incidence ratio (SIR) 35.88; 95% CI, 24.01-51.58)was suggested [24].However, the hazard ratios (HR) in morphea patients compared to controls (without autoimmune disease) were 0.47 (95% CI, 0.12-1.87)for breast cancer, 1.05 (95% CI, 0.15-7.49)for endometrial and 1.09 (95% CI, 0.62-1.93)for other female genital cancers.Adjustments for multiple confounders (e.g., sociodemographic factors, reproductive and gynecologic history, and proxy for life habits) were made.
A cross-sectional study used agglomerated data from the John Hopkins hospital records to compare morphea patients with the general pool of patients between 2012 and 2018.Morphea patients were more likely to be diagnosed with melanoma with an OR of 6.6 (95% CI, 4.1-10.9),SCC (OR 12.8; 95% CI, 4.1-10.9)and BCC (OR 13.1; 95% CI, 9.7-17.5)compared to the control group [14].The risk of developing skin cancer in morphea patients remained after adjusting for race.However, this study was cross-sectional and hence the temporal relationship was not established.Adjustment for other confounders such as age, sex and history of sun exposure was not performed.

The Risk of Cancer in EF Patients
Seven articles reported on a new onset of cancer (3 or more years after diagnosis) in EF patients.All the articles were case reports (7/7).All EF cases were confirmed by histopathology.EF was limited to the extremities in 4/7 patients and generalized in 3/7 patients.Four patients were females (57.1%).The data on race were lacking.The mean age at cancer diagnosis was 69 years old (SD, 7.7, [n = 7]).The mean time to malignancy after EF onset was 3.9 years (SD, 15.7, [n = 7]).Hematological malignancies were seen in 5/7 patients (71.4%), 1 patient developed a solid organ malignancy, and another patient had a non-melanoma skin cancer.
Hematological malignancies were seen in 62.5% of cases (30/48), followed by solid malignancies (16/48 or 33.3%), one patient developed both solid and hematological malignancies and one patient had non-melanoma skin cancer.
Among the three observational studies, one was cross-sectional and two were retrospective single center.A cross-sectional study conducted in the Netherlands reported that 2/35 patients developed paraneoplastic EF.These malignancies were prostate carcinoma and intestinal carcinoid tumour.However, the timing between the two diagnoses was not mentioned [25].
Two retrospective chart reviews were conducted at the Mayo Clinic.The first study published in 1988 included 52 EF patients and reported that 7.7% of EF patients had an associated malignancy.Precisely, three were diagnosed with hematological malignancy within 1 year of EF and one with breast carcinoma (EF resolved spontaneously following mastectomy) [26].The second study reported a 13.4% risk of associated malignancy among 89 EF patients diagnosed from 1997 to 2016.Of these, six were hematologic and six were solid tumors [27].
Most morphea cases occurred after radiation therapy (138/212 or 65.0%) followed by chemotherapy (18/212 or 8.5%) and immunotherapy with immune checkpoint inhibitors (ICIs) (12/212 patients or 5.7%), whereas surgery induced morphea in one patient.The type of morphea is described in Table 1 according to cancer therapy.In 20.3% of patients (43/212), morphea occurred in the context of a multimodal cancer treatment where radiotherapy and/or chemotherapy/targeted agents and/or ICIs were combined.Table S2 presents multimodal cancer treatments.The mean time from treatment to morphea onset was 3.1 years for radiotherapy, 1.6 years for chemotherapy and 0.8 years for ICIs (Table 1).Pemetrexed (7/18 or 38.9%) and docetaxel (5/18 or 27.8%) were the most common chemotherapeutic agents associated with morphea whereas nivolumab (6/12 or 50.0%) and pembrolizumab (4/12 or 33.3%) were the most common ICIs.Of interest, no published cases were identified following CTLA-4 inhibitors.Among nine case series published, several articles attempted to estimate the incidence of radiation-included morphea among all patients undergoing radiotherapy by using as denominator the approximate number of patients they believed they had seen in their department with incidence rates varying from 0.025% to 0.26% [28][29][30].While these incidence rates were frequently recited in the literature, they should be interpreted with caution as the real denominator was not known in either of the studies.We identified only one study (a retrospective cohort from Austria) that assessed the cumulative incidence of radiationinduced morphea among 2268 breast cancer patients between 2009 and 2018.Six patients developed morphea with a cumulative incidence of 0.26% (95% CI; 0.24-0.28),which equals one morphea case per 378 post-radiated patients [31].In all cases, morphea was localized to the breast (either unilateral or bilateral) and appeared 3-10 months following radiation.No association with radiation parameters was seen.
A multicenter retrospective chart review on radiation-induced morphea was conducted at Yale New Haven Hospital, Northwestern Memorial Hospital and Stanford University between 2000 and 2018.The medical record search yielded 25 cases.Most were females (23/25 or 92.0%) with invasive ductal carcinoma (19/25 or 76.0%).The mean latency period from radiation treatment was 35.1 months.Eleven patients (11/25 or 44.0%) had coexisting autoimmune diseases (six patients had rheumatoid arthritis).Over 56% (14/25) of patients developed lesions outside of the radiation field.Among these 14 patients, 64.3% (9/14) had pre-existing autoimmunity.Among 10 patients with severe radiation-induced morphea, risk factors that correlated with disease severity were autoimmunity, smoking history, and breast implantation [32].

The Risk of Developing EF in Patients Following Cancer Therapy
Twenty articles reported the development of EF in patients who had previously received cancer treatment.Of these, 19 were case reports (95.0%), and 1 (5.0%) was an observational study.In total, 24 EF patients were included.In 79.2% of cases (19/24), the diagnosis was confirmed by histopathology.Most cases were limited to the extremities (14/24 or 58.3%), followed by the entire body (6/24 or 25.0%) and the trunk (2/24 or 8.3%).Thirteen patients (54.2%) were female.Among five reported cases, all patients were White.Mean age at cancer diagnosis was 56.8 years old (SD, 14.8, [n = 14]).Mean time to EF onset after treatment initiation was 11.5 months (SD, 6.1, [n = 21]).
Reported cancers were predominantly solid malignancies (20/24 or 83.3%), followed by non-melanoma skin cancers (2/24, 8.3%) and only one hematological malignancy (1/24 or 4.2%).The most common drugs associated with EF development were ICIs (17/24 or 70.8%).Specifically, four cases occurred after nivolumab, four after pembrolizumab, three following a combination of ICIs, four after combination of ICIs and chemotherapy and two with ICIs and radiotherapy.As for morphea, no cases were identified due to CTLA-4 inhibitors as monotherapy.Only two patients developed EF after radiation therapy and two after receiving tamoxifen.
An observational study from Israel published in 2018 reported rheumatic manifestations in 14/400 patients treated with ICIs.Of these, one patient developed EF after 8 months of pembrolizumab for melanoma [33].

Discussion
In this scoping review, we aimed to address the association between morphea/EF and malignancy.Specifically, we sought to answer the following questions: (1) Are patients with morphea/EF at an increased risk of malignancy?(2) Can morphea/EF present as a paraneoplastic phenomenon?(3) What are the prevalence and the culprits of morphea/EF arising due to cancer therapy?
The data regarding the risk of developing secondary malignancy in morphea/EF patients are limited.In morphea, only three observational studies were identified looking specifically for breast/gynecologic malignancies, pancreatic cancer, and skin cancer.Overall, there was no evidence to suggest an increased risk of breast/gynecologic malignancies.However, a ~30% increased risk of pancreatic cancer was suggested.Similarly, an increased risk of melanoma (OR ~6) and non-melanoma skin cancers (OR up to 13) was documented in one study.When looking at the patient characteristics of who developed cancer, generalized and pansclerotic morphea comprised over 2 /3 of patients.Fortunately, among 331 morphea patients who developed cancer, only two patients developed cancer during adolescence and none during childhood.While the mean age at cancer diagnosis was 38.8 years, there are not enough data to suggest that morphea patients may be diagnosed with cancer at a younger age.In EF, only seven case reports of subsequent malignancy were identified.
An increased risk of cancer has indeed been documented in many other systemic autoimmune rheumatic diseases such as systemic lupus erythematosus and SSc [34,35].The risk is likely multifactorial, driven by chronic inflammation, oxidative stress, decreased immune surveillance, the use of systemic immunosuppressive therapies and external triggers associated with these conditions (e.g., silica or solvents in context of SSc) [18,36,37].Chronic fibrotic diseases (e.g., morphea, SSc and scars) may carry an additional risk due to fibrogenesis and disruption of normal tissue architecture, creating favorable conditions for the growth and spread of cancer cells [38][39][40].However, besides the development of SCC in chronic scars (i.e., Marjolin's ulcer), whether skin cancer predominantly affects fibrotic skin in morphea patients' needs further research.Hence, it is plausible that the most severe forms of morphea are particularly at risk of cancer [41].While additional data are needed to address the risk of cancer in morphea/EF patients, we believe that a total body skin examination is warranted to monitor for skin cancer development during the long-term follow-up of morphea patients, particularly with more severe phenotypes.There are insufficient data to recommend additional screening, hence it should be guided by clinical history and individual risk factors.
Contrary to the observation of more morphea patients being at an increased risk of developing cancer compared to EF patients, an inverse finding was observed regarding morphea/EF presenting as a paraneoplastic phenomenon.Paraneoplastic morphea was anecdotally reported in 18 patients, 11 of whom had a generalized subtype.On the other hand, there are more data regarding paraneoplastic EF, which occurs in ~10% of all EF patients, most often in association with hematologic malignancies [26,27,42,43].The pathogenesis of paraneoplastic EF remains unknown.However, some authors hypothesized a shared immune dysregulation and neoantigen-induced T-cell response with type 2 skewing (e.g., IL-3/5 cytokines, eosinophilia) [44,45].However, additional studies are required to confirm the incidence of paraneoplastic EF and elucidate the associated malignancies, clinical characteristics of patients at risk and its pathogenesis.For now, we believe that a narrow workup for hematologic malignancy would be prudent in all patients (i.e., complete blood count, smear, lactate dehydrogenase, protein electrophoresis), and further paraneoplastic workup may be guided by complete history and physical examination.
While most of the studies identified in this scoping review focused on the development of morphea and EF following cancer therapy, only one study looked at the cumulative incidence focusing on radiation-induced morphea in breast cancer patients, with incidence being 0.26% [31].Additional studies attempted to estimate the incidence of radiation-induced morphea.However, they used case series as a design without a precise denominator, but their incidence varied similarly between 0.025% to 0.26% [28][29][30].While the cumulative incidence of post-radiation morphea is low, it is >100 times higher than the cumulative lifetime prevalence estimates in the general population (200 per 100,000 people) [1,2].There was no incidence or prevalence data regarding the risk of morphea following other cancer therapies, such as chemotherapy, hormonal therapy or ICIs.The mean latency period for morphea varied according to the type of cancer treatment, with a trend for faster onset following ICIs.
Two-thirds of morphea cases reported were induced by radiotherapy, with a mean time to morphea onset of 3.2 years.Timing may help to distinguish morphea from radiation dermatitis, which appears within the first weeks of treatment and is considered an acute side effect [46].Most radiation-induced cases were localized to the radiation field and were circumscribed morphea.However, in patients with a history of autoimmunity (e.g., rheumatoid arthritis or positive ANA antibodies), morphea beyond the radiation field was common.Chemotherapy-induced morphea was reported in 14 patients with a mean time to morphea onset of 1.7 years.In half of the cases, morphea was generalized, pansclerotic or mixed.A commonly described scenario was a patient with symmetric bilateral limb involvement (e.g., generalized symmetric morphea subtype).With immunotherapyinduced morphea, the mean time to morphea onset was 8 months, which indicates a rapid manifestation of morphea after ICIs initiation.All of the immunotherapy-induced cases were reported with programmed cell death protein-1 (PD-1) inhibitors and generally had similar clinical features (demographics, subtype) to idiopathic morphea.
Most EF cases were triggered by ICIs (70.8% of patients) and similarly occurred following PD-1 inhibitors (e.g., nivolumab and pembrolizumab).It is unknown why all cases of morphea/EF were related to PD-1 blockers, and none occurred secondary to CTLA-4 inhibition.However, as CTLA-4 and PD-1 inhibitors target different checkpoints in the immune system, this difference could contribute to morphea/EF onset.CTLA-4 inhibitors block CTLA protein, thereby attenuating inhibition of early T cell activation [47].PD-1 inhibitors, on the other hand, target the PD-1 protein expressed primarily on the surface of activated effector T-cells in peripheral tissues [47].Therefore, the phase at which these ICIs mostly intervene in the immune response may explain the difference observed in the onset or absence of morphea/EF [47].This should be further studied.
Our study presents several limitations that are inherent to the nature of a scoping review.As scoping reviews prioritize mapping the literature rather than conducting detailed epidemiological analyses, this limits our ability to draw definitive epidemiological conclusions.Another inherent limitation is the lack of quality assessment for the included studies.This limitation restricts our ability to evaluate the methodological rigour or risk of bias in our included studies.Moreover, despite our efforts to contact authors twice when the articles were unavailable, a few articles could not be obtained, which introduces the possibility of missing eligible studies.Despite this, we believe we were able to capture

Figure 1 .
Figure 1.The Preferred Reporting Items of Systematic Reviews and Meta-Analysis (PRISMA) guidelines for Scoping Reviews Search Flow Diagram.* While 201 articles were included, 1 article was discussed in 2 sections.

Figure 1 .
Figure 1.The Preferred Reporting Items of Systematic Reviews and Meta-Analysis (PRISMA) guidelines for Scoping Reviews Search Flow Diagram.* While 201 articles were included, 1 article was discussed in 2 sections.

Table 1 .
Type of Morphea According to Cancer Treatment.